The effects of chronic alcohol consumption and of alcohol, in vitro, on the structure and function of mitochondrial membranes from liver, brain and the erythrocyte plasma membrane, will be investigated. Studies with mitochondria from rat liver and brain will focus on the mechanism of the alcohol-induced reduction in the efficiency of oxidative phosphorylation. In addition to conventional assays of enzyme activity, 31P-NMR, phosphorescence anisotropy, fluorescence energy transfer and other biophysical techniques will be utilized in these studies. The effect of alcohol on the metabolism of amino-acid neurotransmitters in brain mitochondria will also be investigated. The partition of ethanol, anesthetics and cholesterol into various membranes will be studied in great detail, using radioactive, fluorescence quenching and NMR techniques. These studies should lead to a better understanding of the mechanisms by which the reduced partition of ethanol, which is postulated to lead to membrane resistance (tolerance), is acquired during chronic alcohol ingestion. Studies of the effect of alcohol on cell cultures will indicate whether cellular mechanisms are sufficient to induce membrane tolerance and dependence. The effect of alcohol on membrane surface charge, and particularly on Ca2+ binding and distribution, will be investigated in relationship to the role of the dielectric constant in the effect of alcohol on Ca2+ metabolism. It is hoped that this investigation will lead to a better understanding of the mechanism of the adaptation of membranes to chronic alcohol ingestion and the development of tolerance and dependence. Such knowledge may lead to new therapeutic strategies in combating chronic alcoholism.